Clinical Trial Database Analyses to Inform Regulatory Guidances: Improving the Efficiency of Schizophrenia Clinical Trials Islam R. Younis, Ph.D. Team Leader Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research US Food and Drug Administration
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Clinical Trial Database Analyses to Inform Regulatory Guidances:
Improving the Efficiency of Schizophrenia Clinical Trials
Islam R. Younis, Ph.D.
Team Leader
Office of Clinical Pharmacology
Office of Translational Sciences
Center for Drug Evaluation and Research
US Food and Drug Administration
2
Disclaimer
• The opinions expressed in this presentation are the presenter’s
and do not necessarily reflect the official views of the United
States Food and Drug Administration (FDA)
• The author has no disclosures related to the content of this
presentation
2
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Motivation
• Schizophrenia is a devastating illness.
• The antipsychotic development programs have been hindered by
many factors:
– Increase in placebo response
– Decrease in trial success rates (Failure Rate = 38%)
– Large dropouts (40% to 50%) in clinical trials.
• Several large pharmaceutical companies have announced plans to
abandon drug development programs in psychiatric diseases
including schizophrenia.
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Project Goal
• The goal of this project is to evaluate alternative
clinical and regulatory endpoints and design elements
that can improve the success of schizophrenia drug
development programs.
– To provide industry with a more attractive development
program while at the same time providing the high
standard evidence of efficacy and safety that the Agency
requires to approve new drugs.
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Specific Objectives
1. Determine the optimal study duration for establishing efficacy
in schizophrenia trials.
2. Explore the utility of items in the PANSS instrument to
optimize signal to noise ratio.
3. Exploring alternative endpoints to evaluate efficacy in
schizophrenia trials.
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Database Building
Key identifier
variables
Efficacy
dataset
Disposition
AE dataset
All registration
trials for Drug A
All registration
trials for Drug B
All registration
trials for Drug N
Master
schizophrenia
database
contains
subject level
information on
longitudinal
PANSS item
scores,
subscale
scores,
demographics,
dosing, AE
Master database contains efficacy and AE information from
Eight Atypical Antipsychotics approved between 2001 and 2015
The database is QC checked and uses uniform data variables across all
8 NDA’s
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Final Database
Number of NDA’s in the Database (2001-2015) 8
Total Number of Trials 32
Total Number of Treatment Arms 86
Total Number of Subjects 14219
Randomized to Placebo 3533
Randomized to Drug Treatment 10686
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Objective #1. Shortening Trial Duration
• Literature data suggest week 2 response to antipsychotic
treatments can predict response at weeks 4 and 6
• Kinon et al proposed that trial duration from 6 weeks to 2 to 4
weeks may minimize dropouts, leading to a more representative
group of patients completing the study and more robust
conclusions (minimal data imputation)
• Additional benefits for shortening trial duration:
– Reducing exposure to experimental medication (and placebo)
– Allowing exploration of more doses in a trial
– Reducing the cost of drug development program
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Typical Design of Efficacy Trial
Baseline Week 1
End Point
Week 2 Week 3 Week 4 Week 5 Week 6
Drug
Placebo
Active Arm
R
Endpoint: Change from baseline in Positive and Negative Syndrome Scale (PANSS)
Positive Scale (N=7)
Negative Scale (N=7)
General Psychopathology (N=16)
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Longitudinal Mean Change from Baseline in Total PANSS
Treatment discrimination from placebo evident
in change from baseline-total PANSS from Week 1 onwards
www.fda.gov
Placebo
Treatment
Active Control
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Correlation between Early and Late Endpoint
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Effect at Week 4 vs. Week 6
Week 6
No of Positive Treatment Arms: 11 No of Positive Treatment Arms: 10
www.fda.gov
Mixed model repeated measures analysis was used to estimate treatment effects by trials
and assess statistical significance at different time points
Week 4
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Concordance Rate
Week
1,2,3,4 No
No
www.fda.gov
Week Concordance Rate Discordance Rate
Week 1 vs Week 6 68% 32%
Week 2 vs Week 6 74% 26%
Week 3 vs Week 6 83% 17%
Week 4 vs Week 6 93% (80/86) 7% (6/86)
[FN = 6]
Week 6 Results
Positive Negative
Positive Concordance Discordance (False +ve)
Negative Discordance (False –ve) Concordance
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Concordance Rates by Drug
www.fda.gov
15
Adverse Events (Week 4 vs. Week 6)
www.fda.gov
Week 6 Week 4
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Akathisia Somnolence
Agitation TachycardiaHeadache
www.fda.gov
EPS
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Time to Reach Steady State
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Shortening Trial Duration to 4 Weeks is Feasible
• Conclusions based on:
– Analysis of change from baseline in Total PANSS data from